The invention relates to methods of identifying compounds for the treatment of Alzheimer's disease (AD) and non-AD neuronal atrophy-associated dementia.
Rare early-onset forms of familial Alzheimer's disease (FAD) are inherited as autosomal dominant diseases. Mutations in the broadly expressed transmembrane amyloid precursor protein (APP), although extremely rare, were the first FAD-causing genetic defects identified and are associated with abundant cerebrovascular β-amyloid, a major neuropathological feature of AD. All of these mutations appear to influence the proteolytic processing of APP, modifying the amount of and/or length of the Aβ peptide, the major component of β-amyloid. Mutations of the presenilin genes (PS1 and PS2) were more recently identified as causing more than half of all cases of early-onset FAD. Among other proposed effects, presenilin mutations influence the production of the 42 and 40 kDa forms of Aβ1(Aβ1-42 and Aβ1-40) by favoring the former. The existing animal models of AD, other than aged primates or dogs, make use of mutant APP and mutant presenilin to create mice that deposit β-amyloid.
An early hallmark of AD pathology is activation of the lysosomal system (LS)(Cataldo et al., Neuron 14:671–680, 1995; Nixon et al., Trends Neurosci. 18:489–496, 1995; Cataldo et al., Adv. Exp. Med. Biol. 389:271–280, 1996; Cataldo et al., J. Neurosci. 16:186–199, 1996). Despite concerted efforts, there is an incomplete understanding of the mechanism of LS activation and its role in AD pathogenesis.
Thus, there is a need to define the pathogenic significance of the early and progressive activation of the LS in neuronal atrophy-associated dementias such as AD. There is also a need for assays for compounds that are useful for the treatment of neuronal atrophy-associated dementias, and particularly for compounds that reduce Aβ formation. Moreover, there is a need for better tools for the diagnosis of neuronal atrophy-associated dementias.